The use of various nucleoside analogs as agents for the treatment of cancer, fungal infections, bacterial infections and viral infections is not new. Most of the present therapies involving nucleoside analogs rely on nucleosides which generally have a natural "D" configuration about the sugar synthon. Although there are a number of reasons for the limitations associated with the use of nucleoside analogs as therapeutic agents including unfavorable pharmacokinetics and lack of specificity, it is the underlying toxicity of the therapeutic nucleoside analogs to the host which is perhaps primarily responsible for the limited use of these agents. One of the primary mechanisms for nucleoside toxicity in humans is by inhibition of mitochondrial DNA synthesis.
In the treatment of viral infections, the treatment of Herpes Simplex Virus (HSV), related Herpes infections and Human Immunodeficiency Virus (HIV) with nucleoside analogs is now part of the armamentarium of the medical practitioner. A viral disease which recently has been studied ingreat detail and treated with only limited success is AIDS. AIDS is a generally fatal disease caused by a human pathogenic retrovirus known as human T-lymphotropic virus type III (HTLV III), lymphadenopathy-associated virus (LAV) or human immunodeficiency virus (HIV).
A number of nucleosides have played important roles in developing a treatment regimen for HIV infections. 3'-azido-3'deoxythymidine (AZT) is a prime example, although recent reports raise some doubts about its effectiveness. A number of 2',3'-dideoxynucleoside analogs also have exhibited significant activity against human immunodeficiency virus (HIV), including 3'-deoxy-2',3'-didehydrothymidine (D4T), carbocyclic analog of 2',3'-dideoxy-2',3'-didehydroguanosine (Carbovir), 2',3'-dideoxycytidine (ddC), 3'-azido-2',3'-dideoxyguanosine (AZG), 2',3'-dideoxyinosine (DDI), 2',3'-dideoxy-2',3'-didehydrocytidine (D4C), 3'-fluoro-2',3'-dideoxyadenosine, 3'-fluoro-3'-deoxythymidine and 3'-azido-2',3'-dideoxyuridine. See, for example, Larder, et al., Antimicrob. Agents Chemother., 34, 436 (1990).
A number of the above-described nucleoside analogs have shown some promise in the treatment of AIDS or as inhibitors of HIV. These include 3'-azido-3'deoxythymidine (AZT) as well as the .beta.-D-2',3'-Dideoxynucleosides, for example, .beta.-D-2',3'-dideoxycytidine (ddC) and .beta.-D-2',3'-dideoxyadenosine and .beta.-D-2,'3'-dideoxyinosine (DDI), among other nucleosides (Richman, et al., N. Engl. J. Med., 317, 192, 1987; and Mitsuya, Proc. Nat. Acad. Sci. USA, 83, 1911, 1986). Other nucleoside agents which are at various clinical states of use for the treatment of HIV include .beta.-D-2',3'-didehydro-3'-deoxy-thymidine (D4T), 3'-azido-2',3'-dideoxyuridine (AzddU, CS-87, AZDU) and 3'-fluoro-3'-deoxythymidine (FLT).
In currently available therapeutics, the only approved compounds for use as anti-HIV agents alone are AZT and DDI (generally, DDI is administered to those patients who, for some reason, are intolerant to the administration of AZT). An aDDItional agent, ddC, has received approval for use as an anti-HIV agent in combination with AZT.
All of the above described anti-HIV nucleoside agents are used in the form of their naturally occuring enantiomers (D sugars). All of the approved anti-HIV nucleoside agents exhibit significant side effects in the form of toxicity. In aDDItion, resistance to these agents has recently emerged.
Thus, the search has continued to find agents which exhibit significant anti-HIV activity with reduced toxicity. Recent developments have focused on certain nucleoside analogs having an unnatural "L" configuration about the sugar synthon rather than the natural "D" configuration. These agents, especially .beta.-L-2',3'-dideoxycytidine (.beta.-L-ddC) and .beta.-L-5-fluoro-2',3'-dideoxycytidine (.beta.-L-FddC) have exhibited anti-HIV activity. At the same time that these "L" nucleoside analogs exhibit significant anti-HIV activity, in vivo studies have shown these same nucleoside analogs to exhibit significantly reduced toxicity to the host compared to anti-HIV nucleoside agents based upon the natural "D" configuration of the sugar synthon. Further studies evidence that a combination of an effective amount of at least one of the "D" nucleoside analogs with a toxicity reducing amount of at least one nucleoside compound having the unnatural "L" configuration produces a therapeutic composition exhibiting unexpectedly reduced toxicity to the host. In those instances where the "L" nucleoside has the same therapeutic activity as the "D" nucleoside analog to be administered, the result will be a therapeutic effect will be an increased therapeutic activity in combination with unexpectedly diminished toxicity. The unexpected reduction of toxicity caused by nucleoside compounds having the natural "D" configuration of the sugar synthon is a primary feature of the present invention.